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"Cramer, S."
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Deletion of Fmr1 Alters Function and Synaptic Inputs in the Auditory Brainstem
Fragile X Syndrome (FXS), a neurodevelopmental disorder, is the most prevalent single-gene cause of autism spectrum disorder. Autism has been associated with impaired auditory processing, abnormalities in the auditory brainstem response (ABR), and reduced cell number and size in the auditory brainstem nuclei. FXS is characterized by elevated cortical responses to sound stimuli, with some evidence for aberrant ABRs. Here, we assessed ABRs and auditory brainstem anatomy in Fmr1-/- mice, an animal model of FXS. We found that Fmr1-/- mice showed elevated response thresholds to both click and tone stimuli. Amplitudes of ABR responses were reduced in Fmr1-/- mice for early peaks of the ABR. The growth of the peak I response with sound intensity was less steep in mutants that in wild type mice. In contrast, amplitudes and response growth in peaks IV and V did not differ between these groups. We did not observe differences in peak latencies or in interpeak latencies. Cell size was reduced in Fmr1-/- mice in the ventral cochlear nucleus (VCN) and in the medial nucleus of the trapezoid body (MNTB). We quantified levels of inhibitory and excitatory synaptic inputs in these nuclei using markers for presynaptic proteins. We measured VGAT and VGLUT immunolabeling in VCN, MNTB, and the lateral superior olive (LSO). VGAT expression in MNTB was significantly greater in the Fmr1-/- mouse than in wild type mice. Together, these observations demonstrate that FXS affects peripheral and central aspects of hearing and alters the balance of excitation and inhibition in the auditory brainstem.
Journal Article
The Portable Emerson
\"A comprehensive collection of writings by \"the most influential writer of the nineteenth century\" (Harold Bloom) Ralph Waldo Emerson's diverse body of work has done more than perhaps any other thinker to shape and define the American mind. Literary giants including Henry David Thoreau, Nathaniel Hawthorne, and Walt Whitman were among Emerson's admirers and proteges, while his central text, Nature, singlehandedly engendered an entire spiritual and intellectual movement in transcendentalism. This long-awaited update-the first in more than thirty years-presents the core of Emerson's writings, including Nature and The American Scholar, along with revelatory journal entries, letters, poetry, and a sermon\"-- Provided by publisher.
Book
The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models
The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT–PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (
P
<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (
P
<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
Journal Article
Inhibition of myostatin prevents microgravity-induced loss of skeletal muscle mass and strength
The microgravity conditions of prolonged spaceflight are known to result in skeletal muscle atrophy that leads to diminished functional performance. To assess if inhibition of the growth factor myostatin has potential to reverse these effects, mice were treated with a myostatin antibody while housed on the International Space Station. Grip strength of ground control mice increased 3.1% compared to baseline values over the 6 weeks of the study, whereas grip strength measured for the first time in space showed flight animals to be -7.8% decreased in strength compared to baseline values. Control mice in space exhibited, compared to ground-based controls, a smaller increase in DEXA-measured muscle mass (+3.9% vs +5.6% respectively) although the difference was not significant. All individual flight limb muscles analyzed (except for the EDL) weighed significantly less than their ground counterparts at the study end (range -4.4% to -28.4%). Treatment with myostatin antibody YN41 was able to prevent many of these space-induced muscle changes. YN41 was able to block the reduction in muscle grip strength caused by spaceflight and was able to significantly increase the weight of all muscles of flight mice (apart from the EDL). Muscles of YN41-treated flight mice weighed as much as muscles from Ground IgG mice, with the exception of the soleus, demonstrating the ability to prevent spaceflight-induced atrophy. Muscle gene expression analysis demonstrated significant effects of microgravity and myostatin inhibition on many genes. Gamt and Actc1 gene expression was modulated by microgravity and YN41 in opposing directions. Myostatin inhibition did not overcome the significant reduction of microgravity on femoral BMD nor did it increase femoral or vertebral BMD in ground control mice. In summary, myostatin inhibition may be an effective countermeasure to detrimental consequences of skeletal muscle under microgravity conditions.
Journal Article
Long-term microglia depletion impairs synapse elimination and auditory brainstem function
Specialized sound localization circuit development requires synapse strengthening, refinement, and pruning. Many of these functions are carried out by microglia, immune cells that aid in regulating neurogenesis, synaptogenesis, apoptosis, and synaptic removal. We previously showed that postnatal treatment with BLZ945 (BLZ), an inhibitor of colony stimulating factor 1 receptor (CSF1R), eliminates microglia in the brainstem and disables calyceal pruning and maturation of astrocytes in the medial nucleus of the trapezoid body (MNTB). BLZ treatment results in elevated hearing thresholds and delayed signal propagation as measured by auditory brainstem responses (ABR). However, when microglia repopulate the brain following the cessation of BLZ, most of the deficits are repaired. It is unknown whether this recovery is achievable without the return of microglia. Here, we induced sustained microglial elimination with a two-drug approach using BLZ and PLX5622 (PLX). We found that BLZ/PLX treated mice had impaired calyceal pruning, diminished astrocytic GFAP in the lateral, low frequency, region of MNTB, and elevated glycine transporter 2 (GLYT2) levels. BLZ/PLX treated mice had elevated hearing thresholds, diminished peak amplitudes, and altered latencies and inter-peak latencies. These findings suggest that microglia are required to repopulate the brain in order to rectify deficits from their ablation.
Journal Article
Ocean overturning since the Late Cretaceous: Inferences from a new benthic foraminiferal isotope compilation
Benthic foraminiferal oxygen isotopic ( 18 O) and carbon isotopic ( 13 C) trends, constructed from compilations of data series from multiple ocean sites, provide one of the primary means of reconstructing changes in the ocean interior. These records are also widely used as a general climate indicator for comparison with local and more specific marine and terrestrial climate proxy records. We present new benthic foraminiferal 18 O and 13 C compilations for individual ocean basins that provide a robust estimate of benthic foraminiferal stable isotopic variations to ~80 Ma and tentatively to ~110 Ma. First-order variations in interbasinal isotopic gradients delineate transitions from interior ocean heterogeneity during the Late Cretaceous (>~65 Ma) to early Paleogene (3565 Ma) homogeneity and a return to heterogeneity in the late Paleogeneearly Neogene (350 Ma). We propose that these transitions reflect alterations in a first-order characteristic of ocean circulation: the ability of winds to make water in the deep ocean circulate. We document the initiation of large interbasinal 18 O gradients in the early Oligocene and link the variations in interbasinal 18 O gradients from the middle Eocene to Oligocene with the increasing influence of wind-driven mixing due to the gradual tectonic opening of Southern Ocean passages and initiation and strengthening of the Antarctic Circumpolar Current. The role of wind-driven upwelling, possibly associated with a Tethyan Circumequatorial Current, in controlling Late Cretaceous interior ocean heterogeneity should be the subject of further research.
Journal Article
Phanerozoic Record of Global Sea-Level Change
We review Phanerozoic sea-level changes [543 million years ago (Ma) to the present] on various time scales and present a new sea-level record for the past 100 million years (My). Long-term sea level peaked at 100 ± 50 meters during the Cretaceous, implying that ocean-crust production rates were much lower than previously inferred. Sea level mirrors oxygen isotope variations, reflecting ice-volume change on the 10⁴- to 10⁶-year scale, but a link between oxygen isotope and sea level on the 10⁷-year scale must be due to temperature changes that we attribute to tectonically controlled carbon dioxide variations. Sea-level change has influenced phytoplankton evolution, ocean chemistry, and the loci of carbonate, organic carbon, and siliciclastic sediment burial. Over the past 100 My, sea-level changes reflect global climate evolution from a time of ephemeral Antarctic ice sheets (100 to 33 Ma), through a time of large ice sheets primarily in Antarctica (33 to 2.5 Ma), to a world with large Antarctic and large, variable Northern Hemisphere ice sheets (2.5 Ma to the present).
Journal Article
Selection Progress for Resistance to Fusarium Basal Rot in Short-Day Onions Using Artificial Inoculation Mature Bulb Screening
Fusarium basal rot (FBR), caused by a soil-borne fungus, Fusarium oxysporum f. sp. cepae (FOC), is a major disease hindering onion production worldwide. This study was conducted to evaluate the initial and the most advanced selected populations of seven open-pollinated short-day onion cultivars for FBR susceptibility, along with two check cultivars using the conidial inoculation of mature bulbs for two consecutive years. The artificial inoculation of mature bulbs was carried out by applying a virulent FOC isolate ‘CSC 515’ at a final concentration of 3.0 × 104 spores mL−1 to the transversely cut basal plates of onion bulbs. The basal plates of 20 arbitrarily chosen bulbs per plot were recut after 20 days of incubation and then were rated for FBR severity using a rating scale of 1 (no disease) to 9 (≥70% of the basal plate is infected). The bulbs with a rating of 1 were saved and then bulked to form the seeds for the next generation. The selected populations exhibited a variable response for FBR severity when evaluated over two years, with an improvement in the most advanced selections observed for a majority of the cultivars. For example, the advanced selections of ‘NuMex Sweetpak’ exceeded the partially resistant check ‘Serrana’ in their levels of resistance when both were evaluated in the second year. A conidial inoculation can be effective in the development of FBR-resistant cultivars. In addition, this inoculation method can accelerate breeding efforts by determining the genetic mechanism(s) responsible for FBR resistance, locating quantitative trait loci, and facilitating marker-assisted selection.
Journal Article
Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease
Introduction
Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes.
Methods
Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA fragments, and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n = 69) or without DKD (n = 405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR), and the plasma proteome.
Results
In total seven sncRNAs were negatively associated with prevalent DKD (all P
FDR
≤ 0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825 | DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3).
Conclusion
We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results show that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.
Journal Article